Nickel-Catalyzed Denitrogenative Annulation of 1,2,3-Benzotriazin-4-(3H)-ones with Benzynes for Construction of Phenanthridinone Scaffolds

Article abstract of DOI:10.1002/adsc.201701143

The synthesis of phenanthridinones via denitrogenative annulation of 1,2,3-benzotriazin-4-(3H)-ones with arynes catalysed by Ni(0)/dppm was successfully developed. A variety of phenanthridinones were prepared in good to excellent yields. Based on this method, nature product, N-methylcrinasidine, was synthesized. (Figure presented.).

Full text of DOI:10.1002/adsc.201701143

Title: Nickel-Catalyzed Denitrogenative Annulation of 1,2,3-
Benzotriazin-4-(3H)-ones with Benzynes for Construction of
Phenanthridinone Scaffolds
Authors: Chien-Hong Cheng, Vijaykumar H. Thorat, Nitinkumar
Satyadev Upadhyay, and Masahiro Murakami
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701143
Link to VoR: http://dx.doi.org/10.1002/adsc.201701143

10.1002/adsc.201701143
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Nickel-Catalyzed Denitrogenative Annulation of 1,2,3-
Benzotriazin-4-(3H)-ones with Benzynes for Construction of
Phenanthridinone Scaffolds
Vijaykumar H.Thorat,a Nitinkumar Satyadev Upadhyay,a Masahiro Murakami,*b and
Chien-Hong Cheng*a
a
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan.
e-mail: chcheng@mx.nthu.edu.tw; Fax: +886-3-5724698; Tel: +886-3-5721454
Department of Synthetic Chemistry and Biological Chemistry Kyoto University, Katsura, Kyoto 615-8510 (Japan).
b
e-mail: murakami@sbchem.kyoto-u.ac.jp; Fax: (+81) 75-383-2748
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
methoxybenzamides with aryl boronic acids and aryl
Abstract. The synthesis of phenanthridinones via
denitrogenative annulation of 1,2,3-benzotriazin-4-(3H)- iodide, respectively, for the synthesis of
ones with arynes catalysed by Ni(0)/dppm was successfully
developed. A variety of phenanthridinones were prepared
in good to excellent yields. Based on this method, nature
product, N-methylcrinasidine, was synthesized.
phenanthridinone derivatives.[5b,c] Recently, Jiao’s
group disclosed a Pd-catalyzed domino process
enabling the transformation of arylcarbamic chlorides
and aryl iodides to phenanthridinone scaffolds.[5d]
Jaganmohan et. al accomplished a Pd-catalyzed
cyclization of benzamides and arynes to give
phenanthrididone derivatives.[12f]
Keywords: nickelacycle; annulation; benzyne; nickel;
phenanthridinone
Transition metal-catalyzed reactions have emerged as
powerful tools for the construction of C-C, C-N and
C-X bonds in organic synthesis.[1] In particular, Rh,
Pd, Ni, Co, Ir and Cu catalysis to build nitrogen
heterocycles, natural products and complex molecular
architectures have gained enormous attention.[1-7]
Phenanthridinone alkaloids are an important class of
compounds and are well recognized for antimalarial,
anti-inflammatory, anticancer and many other
pharmacological properties (Figure 1).[3] Considerable
efforts have been directed towards the synthesis of
Figure 1. Representative phenanthridinone alkaloids.
In recent years, transition metal-catalyzed
denitrogenative annulation of substrates such as
1,2,3-benzotriazin-4-(3H)one, triazole, pyridotriazole,
N-aroylbenzotriazole has drawn considerable
attention.[8-11] Similarly the decarboxylation and
decarbonylation strategy were employed to obtain
various heterocycles by utilizing phthalimides,
phthalic anhydride, isatoic anhydrides, triazole and its
analogues.[9,10] These triazole derivatives served as
precursors for metallocycle formation by the
expulsion of gaseous molecules like N2, CO and CO2.
Upon annulation of the metallocycles with various -
substrates, a diverse heterocycles can be formed.[8-10]
Gevorgyan and co-workers reported a heterocyclic
phenanthridinone analogues.
A
Pd-catalyzed
homocoupling reaction of o-halobenzamide reported
by Kan and aminocarbonylation of unprotected o-
arylaniline with CO was achieved by Zhu.[4a,b]
Similarly, Fagnou and Dong developed a Pd-
catalyzed intramolecular arylation of prefabricated
aryl-substituted amides.[4c,d] Curran and co-workers
reported a silane mediated radical cyclization of
prefunctionlized aromatic amide.[4e] Our group has
succeeded in a Pd-catalyzed multiple C-H/N-H bond
activation and annulation of N-methoxybenzamides
with arenes to give N-methoxyphenanthridinone
under mild reaction conditions and its application to
the synthesis of crinasiadine.[5a] Later, we and Wang
et.al independently achieved a Rh(III) and Pd-
catalyzed dual C-H bond activation of N-
scaffold
accessible
via
rhodium-catalyzed
denitrogenation of pyridotriazole.[8a,d] The work by
1
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10.1002/adsc.201701143
Advanced Synthesis & Catalysis
Murakami et.al. demonstrated a nickel-catalyzed
denitrogenative reaction of triazole, 1,2,3-
because the active Ni(0) was successfully generated
in situ using zinc as the reducing agent. The reaction
did not give the annulation product without 18-
crown-6 which would enhance the benzyne
generation rate by increasing the solubility of KF
through coordination to K+ and thus the F-
concentration (entry 13). Other monodentate
phosphine ligands like PPh3 and P(o-tolyl)3 and
bidentate ligands like, dppp, dppb and dppf did not
provide the desired product (see Supporting
Information (SI) for the detailed optimization studies
page S4). This reveals that an appropriate ligand with
suitable bite angle plausibly plays crucial role during
the course of reaction. Based on the optimization
studies, It appears that the bidentate ligand, dppm, is
important to facilitate the reaction with high yields.
Thus, we choose the Ni(cod)2/dppm system as the
catalyst for the following denitrogenative annulation
reactions.
benzotriazin-4(3H)-ones with internal alkynes and
[10b,8b]
allenes.
Nakamura et.al. found a palladium-
catalyzed denitrogenative indolization of N-
aroylbenzotriazole with alkyne.[10c] Recently, Liu’s
group displayed a Ni(0)-driven chiral denitrogenative
transannulation of 1,2,3-benzotriazin-4(3H)-ones
furnishing axially chiral isoquinolones with excellent
enantioselectivity.[11]
[a,b]
Table 1. Scope of 1,2,3-benzotriazin-4(3H)-one.
Scheme
1.
Synthetic
approaches
towards
phenanthridinones.
3a
Entry Catalyst Ligand
Additives
Solvent
Yield
(%)
Benzyne from o-trimethylsilylphenyl triflate and
fluoride was first discovered by Kobayashi and his
co-workers.[12a] Studies on the application of benzyne
chemistry has gained great attention over the past
years.[12] In particular, transition metal-catalyzed
aryne transformation has extensively investigated.[12-
1
2
3
4
5
6
7
8
[Ni(cod)2] PCy3 KF/18-crown-6
[Ni(cod)2] dppm KF/18-crown-6
[Ni(cod)2] dppm KF/18-crown 6
[Ni(cod)2] dppe KF/18-crown-6
[Ni(cod)2] dppp KF/18-crown-6
THF
THF
THF
THF
THF
ACN
DMF
76
95 (94)
80c
70
trace
80
[Ni(cod)2] dppm
CsF/-
14]
[Ni(cod)2] dppm KF/18-crown-6
[Ni(cod)2] dppm KF/18-crown-6 Dioxane
80
5
As a part of our research in utilizing aryne as
useful substrate for organic synthesis, we report
herein an interesting nickel-catalyzed denitrogenative
annulation of 1,2,3-benzotriazin-4-(3H)-one with
aryne.
9
[Ni(cod)2]
-
KF/18-crown-6
THF
-
10
--
dppm KF/18-crown-6
KF/18-crown-6
THF
THF
ACN
THF
-
-
43
11 [Ni(OTf)2]
12 Nil2/Zn
13 [Ni(cod)2] dppm
[a] Reaction conditions: Unless otherwise mentioned, all reactions
were carried out using 1a (0.10 mmol), 2a (0.15 mmol),
[Ni(cod)2] (10 mol %), ligand (20 mol %), KF (0.3 mmol), 18-
dppm
CsF/-
In this study, N-tolyl-1,2,3-benzotriazin-4-(3H)-one
(1a) is selected as the model substrate which can be
readily prepared from methyl anthranilate in two
steps.[15] The initial investigation was focused on the
activation of the triazo core with nickel complexes.
We found that Ni(cod)2 and a suitable phosphine
ligand is effective for the activation. Thus, treatment
of 1a (0.10 mmol) with benzyne precursor 2a (0.15
mmol) in the presence of Ni(cod)2 (0.010 mmol),
dppm (0.020 mmol), KF (0.30 mmol) and 18-crown-
6 (0.20 mmol) in THF at 100˚C for 12 h afforded the
desired product 3a in 94% isolated yield (Table 1,
entry 2). Upon switching to dppe ligand, the yield of
3a decreased to 70% (entry 4). Also, when 1a was
treated with 2a in acetonitrile (ACN), 3a was
obtained in 80% yield (entry 6). The reaction was
completely ineffective without Ni(cod)2 and a
phosphine ligand. The NiI2/Zn/dppm system is also
active affording 3a in 43% yield (entry 12). This is
KF/-
-
crown-6 (0.2 mmol), solvent (2.0 mL), 100 °C, 12 h, isolated
yield.
[b]
Yields were determined by the 1H NMR integration
method using mesitylene as internal standard; the value in the
parenthesis was isolated yield. [c]The reaction was carried out at
100 °C, 6 h. NiI2 (0.010 mmol) and Zn (0.3 mmol). Dppm =
bis(diphenylphosphino)methane, dppe = bis(diphenylphosphino)-
ethane, dppp = bis(diphenylphosphino)propane.
The annulation protocol was successfully applied to a
wide range of 1,2,3-benzotriazin-4-(3H)-one (1)
(Scheme 1). We first examined the 1,2,3-
benzotriazin-4-(3H)-one substrates having N-aryl
group. Thus, 1a-f with a p-substituted N-aryl reacted
with benzyne smoothly in the presence of nickel
catalyst to give the corresponding phenanthridinones
3a-f in excellent yields (Table 2). For meta and ortho-
substituted-N-aryl 1,2,3-benzotriazin-4-(3H)-one, the
2
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10.1002/adsc.201701143
Advanced Synthesis & Catalysis
catalytic reactions with benzyne also proceeded
effectively to afford the expected products (3g-n) in
good to excellent yields. A close examination of the
results shows that the product yield decreases in the
Surprisingly, N-2-pyridyl moiety did not give the
annulated product 3w. Further, we focused our
attention on the expanding substituents around the
backbone of 1,2,3-benzotriazin-4-(3H)-one. As
expected, a variety of functional groups like fluoro,
methoxy and ester did not alter the course of reaction
and furnished the expected products 3x-3ba in 79-
85% yields. Also, 4-morpholine substituted substrate
1ca underwent annulation smoothly affording 3ca in
good yield. Similarly, substrate 1da reacted
effectively to provide the desired product 3da in 79%
yield. Based on the above results, it appears that the
catalytic reaction is not much affected by the
electronics of substituents around the substrate.
order: para-
>
meta-
>
ortho-substitution.
Furthermore, N-alkyl and N-benzylic 1,2,3-
benzotriazin-4-(3H)-one substrates (1o-1s) also
underwent annulation with benzyne smoothly leading
to the corresponding phenanthridinones (3o-3s) in 85-
94% yields. Similar to N-aryl substituted 1,2,3-
benzotriazin-4-(3H)-one (1), the N-2-naphthyl
substituted substrates 1t reacted
Table 2. The scope of 1,2,3-benzotriazin-4(3H)-one in the
annulation reaction. a,b
Subsequently, we examined the effect of substitution
on the aryne group on the yield of the present nickel-
catalyzed reaction (Table 3). Both electron-donating
and –withdrawing 4,5-disubstituted symmetrical
benzyne 2b and 2c offered products 4ab and 4ac in
high 89 and 84% yields, respectively. Interestingly,
the sterically congested 3,6-dimethyl benzyne (2d)
also reacts smoothly with 1a affording product 4ad in
82%. The indanyl derivative 2e and 1,3-benzodioxole
derivatives 2f furnished products 4ae and 4af in
excellent yields. Furthermore, 2,3-naphthyne
precursor 2g also proceeded well under the reaction
conditions to give 4ag in 88% yield. As expected, the
reaction of 1a with unsymmetrical aryne precursors
3h and 3i afforded two regioisomeric products
4ah/4ah’ and 4ai/4ai’ in moderate combined yields.
Table 3. Scope of 1,2,3-benzotriazin-4(3H)-one in the
annulation reaction. a,b
aReaction conditions: 1a (0.10 mmol), 2a (0.15 mmol),
[Ni(cod)2] (10 mol %), dppm (20 mol %), KF (0.30 mmol),
and 18-crown-6 (0.20 mmol) in THF (2.0 mL) at 100 °C
for 12 h. bisolated yield.
smoothly under the standard catalytic conditions to
give the corresponding N-2-naphthyl product 3t in
89% yield. Further, we studied the substitution effect
at positions 3 and 5 of the N-aryl group using electron
withdrawing groups CF3 and Cl as substituents.
Substrate 1u with two m-CF3 groups failed to give the
desired product, whereas 1v with two m-Cl afforded
the expected product 3v in 88% good yield.
aReaction conditions: 1a (0.10 mmol), 2a (0.15
mmol), [Ni(cod)2] (10 mol %), dppm (20 mol %), KF
3
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10.1002/adsc.201701143
Advanced Synthesis & Catalysis
(0.30 mmol), and 18-crown-6 (0.20 mmol) in THF
(2.0 mL) at 100 °C for 12 h. bisolated yield.
We also conducted a competition experiment between
electron-rich substrate 1z and electron-deficient 1aa
(Scheme 2). Substrate 1aa reacted with benzyne
slightly faster than 1da under the standard conditions.
In agreement with the product yields of 3da and 3aa
in Table 2, the result reveals that the electronics factor
hardly affects the reaction progress.
Scheme 2. Competition Experiment
Scheme 4. Proposed Reaction Mechanism
Coordination of benzyne, generated in situ from 2a
and fluoride, to intermediate A gives intermediate B.
Insertion of the coordinated benzyne to the nickel-
carbon bond of A leading to the formation of a seven
membered nickelacycle C. Finally reductive
elimination provides the final product 3a and
regeneration of the catalyst.[17]
The present annulation can be effectively applied to
the synthesis of medicinally interesting compounds as
well as naturally occurring bioactive molecules. We
have successfully synthesized N-methylchrinasidine
(6aa, Scheme 3) in 84% yield from triazinone 5a and
aryne precursor 2a under the standard reaction
conditions. Since 5a was prepared in one step from
the corresponding commercially available 2-
aminoamide in 80% (see SI), the overall yield of 6aa
is 67%. A traditional method for the synthesis of
nature product 6aa was achieved by Cahiez and his
coworkers using piperonal as the starting material in
8 steps and 39% overall yield.[16a,b] Our approach
appears to give higher yield with less steps compared
with above method. It is noteworthy that several other
reports for the synthesis of N-methylcrinasidine
employing metal-catalyed reactions have appeared
previously.[4d,12f,16]
In summary, we have demonstrated the first nickel-
catalyzed denitrogenative annulation of 1,2,3-
benzotriazin-4-(3H)-one with aryne species providing
an
easy
access
to
structurally
diverse
phenanthridinones. The highlights of the present
approach are one pot synthesis, a wide range of
functional group tolerance and the application of the
methodology to nature product synthesis. Further
investigation on the application of 1,2,3-benzotriazin-
4-(3H)-one and its related analogues is underway in
our laboratory.
Scheme 3. Synthesis of natural product
Experimental Section
General procedure for Ni-catalyzed annulations of
3-(p-tolyl)benzo[d][1,2,3]triazin-4(3H)-one
(1a)
with benzyne (2a): A sealed tube containing 3-(p-
tolyl)benzo[d][1,2,3]triazin-4(3H)-one 1a (0.10 mmol),
Ni(cod)2 (0.010 mmol), dppm (0.020 mmol), KF (0.30
mmol) and 18-crown-6 (0.20 mmol) was evacuated and
purged with nitrogen gas three times. Then, freshly
distilled THF (1 mL) was added and benzyne precursor 2a
(0.15 mol) in THF (1 mL) was added via syringe under
nitrogen atmosphere and the reaction mixture was stirred at
100 °C for 12 h. After 12 h, the mixture was cooled and
diluted with CH2Cl2 (10 mL). The mixture was filtered
through a Celite pad and the Celite pad was washed with
CH2Cl2 (3 × 10 mL). The filtrate was concentrated under
reduced pressure. The residue was purified by silica gel
column chromatography using hexane/ethyl acetate as
eluent to afford the desired pure product 3a (26.8 mg;
94%).
A possible mechanistic pathway for the present
nickel-catalyzed annulation using substrates 1a and
2a as the examples is shown in Scheme 4. Initially,
1a reacts with Ni(0) to form a five-membered
azanickelacycle intermediate A by extrusion of a
molecular nitrogen.
Acknowledgements
We thank the Ministry of Science and Technology of the Republic
of China (MOST 103-2633-M-007-001) for support of this
4
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10.1002/adsc.201701143
Advanced Synthesis & Catalysis
research. V.T thank Ministry of Education for Taiwan
Government scholarship.
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COMMUNICATION
Nickel-Catalyzed Denitrogenative Annulation of
1,2,3-Benzotriazin-4-(3H)-ones with Benzynes for
Construction of Phenanthridinone Scaffolds
Adv. Synth. Catal. Year, Volume, Page – Page
Vijaykumar H.Thorat, Nitinkumar Satyadev
Upadhyay, Masahiro Murakami,* and Chien-Hong
Cheng*
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